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Am J Physiol Heart Circ Physiol (September 18, 2003). doi:10.1152/ajpheart.00664.2003
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Submitted on July 14, 2003
Accepted on September 16, 2003

Endothelin-1 modulates hemoglobin-mediated signaling in cerebrovascular smooth muscle via RhoA/Rho kinase and protein kinase C

Christopher Lan1, Debarsi Das1, Andrew Wloskowicz1, and Bozena Vollrath1*

1 Department of Pharmacology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada

* To whom correspondence should be addressed. E-mail: bozena.vollrath{at}ualberta.ca.

Endothelin-1 (ET-1) and oxyhemoglobin (OxyHb) have been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). However, the contribution of ET-1 to this condition has not been definitely established. In these studies we investigated whether threshold concentration of ET-1 enhances cerebrovascular smooth muscle (CVSM) contraction to OxyHb by activating the RhoA/Rho kinase and protein kinase C (PKC) pathways. CVSM contraction was measured in the endotheliumdenuded rabbit basilar arteries. The cytosolic and particulate fractions of CVSM cells were examined for RhoA and PKC reactivity with specific antibodies using immunoblotting procedures. ET-1 (0.1 nM) alone did not produce any significant contraction, but it markedly potentiated the magnitude (223% of control) and rate (149% of control) of contraction in response to OxyHb that was attenuated by the inhibitors of Rho kinase, Y-27632 and HA-1077. ET-1-mediated potentiation of the contraction was also inhibited by the inhibitors of PKC, Ro-32-0432 and GF 109203X. BQ-123 prevented potentiation of the vasoconstriction mediated by ET-1, indicating that the action of ET-1 was mediated by ETA receptor. Pretreatment with ET-1 significantly enhanced the OxyHb-mediated RhoA translocation in CVSM cells and intact basilar arteries. ET-1 also caused potentiation of the PKC{epsilon} expression in the membranes of CVSM cells exposed to OxyHb for 10 and 60 min, but did not markedly change the distribution of PKC{alpha}. Thus, in CVSM threshold concentration of ET-1 potentiates contraction induced by OxyHb by the RhoA/Rho-kinase and PKC{epsilon}-dependent mechanisms. This process may contribute to the pathological contraction of cerebral arteries observed after SAH. .




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